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Wjg.V26.I32.4817 ISSN 1007-9327 (Print) ISSN 2219-2840 (Online) World Journal of W J G Gastroenterology Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2020 August 28; 26(32): 4817-4832 DOI: 10.3748/wjg.v26.i32.4817 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Case Control Study Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders Suat Saribas, Suleyman Demiryas, Erkan Yilmaz, Omer Uysal, Nuray Kepil, Mehmet Demirci, Reyhan Caliskan, Harika Oyku Dinc, Seher Akkus, Nesrin Gareayaghi, Sahra Kirmusaoglu, Dogukan Ozbey, Hrisi B Tokman, Serdar S Koksal, Ihsan Tasci, Bekir Kocazeybek ORCID number: Suat Saribas 0000- Suat Saribas, Reyhan Caliskan, Harika Oyku Dinc, Seher Akkus, Dogukan Ozbey, Hrisi B Tokman, 0002-4549-3887; Suleyman Demiryas Bekir Kocazeybek, Department of Medical Microbiology, Istanbul University-Cerrahpasa, 0000-0002-0050-9099; Erkan Yilmaz Cerrahpasa Medical Faculty, Istanbul 34098, Turkey 0000-0002-5133-4532; Omer Uysal 0000-0002-8833-697X; Nuray Kepil Suleyman Demiryas, Ihsan Tasci, Department of General Surgery, Istanbul University- 0000-0001-5494-6422; Mehmet Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey Demirci 0000-0001-9670-2426; Reyhan Caliskan 0000-0002-2764- Erkan Yilmaz, Department of Organ Transplantation, HLA Laboratory, Istanbul University- 1823; Harika Oyku Dinc 0000-0003- Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey 3628-7392; Seher Akkus 0000-0002- 9236-2062; Nesrin Gareayaghi 0000- Omer Uysal, Deparment of Biostatistics, Medical School of Bezmialem Vakif University, 0002-0812-1128; Sahra Kirmusaoglu Istanbul 34093, Turkey 0000-0003-3038-1417; Dogukan Ozbey 0000-0002-0596-1551; Hrisi B Nuray Kepil, Department of Pathology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Tokman 0000-0002-2205-5120; Serdar Faculty, Istanbul 34098, Turkey S Koksal 0000-0001-7199-2295; Ihsan Tasci 0000-0002-2891-6200; Bekir Mehmet Demirci, Department of Medical Microbiology, Beykent University Medical Faculty, Kocazeybek 0000-0003-1072-3846. Istanbul 34520, Turkey Author contributions: Saribas S, Nesrin Gareayaghi, Center for Blood, Istanbul Sisli Hamidiye Etfal Training and Research Demiryas S, Ozbey D and Hospital, University of Health Sciences, Istanbul 34360, Turkey Kocazeybek B designed and coordinated the study; Caliskan R, Sahra Kirmusaoglu, Department of Molecular Biology and Genetics, T.C. Halic University, Tasci I, Demirci M, Dinc HO and Faculty of Arts & Sciences, Istanbul 34381, Turkey Kirmusaoglu S performed the Serdar S Koksal, Department of Public Health, Istanbul University-Cerrahpasa, Cerrahpasa experiments, acquired and Medical Faculty, Istanbul 34098, Turkey analyzed data;Yilmaz E, Kepil N,Uysal O, Akkus S, Gareayaghi N Corresponding author: Bekir Kocazeybek, PhD, Full Professor, Professor, Department of interpreted the data; Koksal SS, Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Tokman HB, Saribas S, Kocazeybek Cerrahpasa Street, Istanbul 34098, Turkey. [email protected] B wrote the manuscript; all authors approved the final version of the article. Abstract Supported by the Istanbul BACKGROUND University Research Fund, No. Polymorphisms of human leukocyte antigen (HLA) genes are suggested to 45151. increase the risk of gastric cancer (GC). WJG https://www.wjgnet.com 4817 August 28, 2020 Volume 26 Issue 32 Saribas S et al. HLA polymorphisms in gastrointestinal disorders Institutional review board AIM statement: This study was To investigate the HLA allele frequencies of patients with GC relative to a control reviewed and approved by the group in terms of CagA+ multiple (≥ 2) EPIYA-C repeats. Ethics Committee of the Istanbul METHODS University. The patient group comprised 94 patients [44 GC and 50 duodenal ulcer (DU) patients], and the control group comprised 86 individuals [(50 non-ulcer Informed consent statement: dyspepsia patients and 36 people with asymptomatic Helicobacter pylori (H. pylori) Informed written consent was ]. Polymerase chain reaction was performed for the amplification of the H. pylori obtained from the patients. cagA gene and typing of EPIYA motifs. HLA sequence-specific oligonucleotide Conflict-of-interest statement: The (SSO) typing was performed using Lifecodes SSO typing kits (HLA-A, HLA-B authors have nothing to disclose. HLA-C, HLA-DRB1, and HLA-DQA1-B1 kits). Data sharing statement: No RESULTS additional data are available. The comparison of GC cases in terms of CagA+ multiple (≥ 2) EPIYA-C repeats showed that only the HLA-DQB1*06 allele [odds ratio (OR): 0.37, P = 0.036] was STROBE statement: The guidelines significantly lower, but significance was lost after correction (Pc = 0.1845). The of the STROBE Statement have HLA-DQA1*01 allele had a high ratio in GC cases with multiple EPIYA-C repeats, been adopted. but this was not significant in the univariate analysis. We compared allele frequencies in the DU cases alone and in GC and DU cases together using the Open-Access: This article is an same criterion, and none of the HLA alleles were significantly associated with GC open-access article that was or DU. Also, none of the alleles were detected as independent risk factors after the selected by an in-house editor and multivariate analysis. On the other hand, in a multivariate logistic regression with fully peer-reviewed by external no discriminative criterion, HLA-DQA1*01 (OR = 1.848), HLA-DQB1*06 (OR = reviewers. It is distributed in 1.821) and HLA-A*02 (OR = 1.579) alleles were detected as independent risk accordance with the Creative factors for GC and DU. Commons Attribution NonCommercial (CC BY-NC 4.0) CONCLUSION license, which permits others to None of the HLA alleles were detected as independent risk factors in terms of distribute, remix, adapt, build CagA+ multiple EPIYA-C repeats. However, HLA-DQA1*01, HLA-DQB1*0601, upon this work non-commercially, and HLA-A*2 were independent risk factors with no criterion in the multivariate and license their derivative works analysis. We suggest that the association of these alleles with gastric malignancies on different terms, provided the is not specifically related to cagA and multiple EPIYA C repeats. original work is properly cited and the use is non-commercial. See: htt Key words: Human leukocyte antigen; Helicobacter pylori; Gastric cancer; Duodenal p://creativecommons.org/licenses ulcer; EPIYA; CagA /by-nc/4.0/ ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. Manuscript source: Invited manuscript Core tip: The development of gastric cancer (GC) is suggested to be related to the Received: March 12, 2020 interactions of bacterial virulence and host genetic factors with the immune response of the Peer-review started: March 12, 2020 host. The effects of polymorphisms in the human leukocyte antigen (HLA) gene may First decision: May 15, 2020 regulate the degree of the inflammatory response of the host leading to the gastric Revised: July 2, 2020 malignancies. We could not detect any prominent HLA alleles between the patient and Accepted: August 20, 2020 control groups in terms of CagA+ multiple (≥ 2) EPIYA-C repeat numbers. HLA- DQA1*01, HLA-DQB1*06, and HLA-A*02 were detected as independent risk factors for Article in press: August 20, 2020 the risk of GC and duodenal ulcer with no criterion in multivariate analyses. We suggest Published online: August 28, 2020 that the association of these alleles with gastric malignancies is not specifically related to P-Reviewer: de Melo FF, Du Y, Sun cagA and multiple EPIYA C repeats. X S-Editor: Liu M Citation: Saribas S, Demiryas S, Yilmaz E, Uysal O, Kepil N, Demirci M, Caliskan R, Dinc L-Editor: A HO, Akkus S, Gareayaghi N, Kirmusaoglu S, Ozbey D, Tokman HB, Koksal SS, Tasci I, P-Editor: Li JH Kocazeybek B. Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders. World J Gastroenterol 2020; 26(32): 4817-4832 URL: https://www.wjgnet.com/1007-9327/full/v26/i32/4817.htm DOI: https://dx.doi.org/10.3748/wjg.v26.i32.4817 WJG https://www.wjgnet.com 4818 August 28, 2020 Volume 26 Issue 32 Saribas S et al. HLA polymorphisms in gastrointestinal disorders INTRODUCTION Gastric cancer (GC) is the third most common cause of death among all cancer types (8.2% of all cancers, 2018, World Health Organization)[1]. GC has been closely associated with Helicobacter pylori (H. pylori) infections, which generally cause mild gastrointestinal symptoms. However, in a few infected patients, they may progress to peptic ulcer (PU) (10%-15%) or GC (1%-3%)[2]. Generally, H. pylori infections cause gastric inflammation and a chronic inflammatory response that result in progressive mucosal damage. Eventually, the gastric mucosa transforms into metaplastic and dysplastic epithelia, which leads to gastric adenocarcinomas[3]. The development of GC is suggested to be related to the interactions between bacterial virulence factors, host genetic factors such as the human leukocyte antigen (HLA) gene, the immune response of the host, and environmental factors such as diet and smoking[4]. Some of the host factors may be related to polymorphisms genes such as HLA genes, which regulate the strength of the inflammatory response and influence the probability of specific clinical results[5]. CagA is among the most important virulence factors specific to H. pylori and is delivered into the gastric epithelium cells by the type IV secretion system (T4SS) of the bacterium. It is involved with
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